Clinical trials to assess adjuvant therapeutics for severe malaria
Abstract Despite potent anti-malarial treatment, mortality rates associated with severe falciparum malaria remain high. To attempt to improve outcome, several trials have assessed a variety of potential adjunctive therapeutics, however none to date has been shown to be beneficial. This may be due, a...
Published in: | Malaria Journal |
---|---|
Main Authors: | , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
BMC
2020
|
Subjects: | |
Online Access: | https://doi.org/10.1186/s12936-020-03340-3 https://doaj.org/article/86d42e349f614e7db049f4afa0bd9cdb |
id |
ftdoajarticles:oai:doaj.org/article:86d42e349f614e7db049f4afa0bd9cdb |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:86d42e349f614e7db049f4afa0bd9cdb 2023-05-15T15:16:21+02:00 Clinical trials to assess adjuvant therapeutics for severe malaria Rosauro Varo Clara Erice Sydney Johnson Quique Bassat Kevin C. Kain 2020-07-01T00:00:00Z https://doi.org/10.1186/s12936-020-03340-3 https://doaj.org/article/86d42e349f614e7db049f4afa0bd9cdb EN eng BMC http://link.springer.com/article/10.1186/s12936-020-03340-3 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-020-03340-3 1475-2875 https://doaj.org/article/86d42e349f614e7db049f4afa0bd9cdb Malaria Journal, Vol 19, Iss 1, Pp 1-6 (2020) Severe malaria Angiopoietin-2 Immune and endothelial activation Microvascular dysfunction Host-biomarkers Surrogate endpoints Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2020 ftdoajarticles https://doi.org/10.1186/s12936-020-03340-3 2022-12-31T01:12:08Z Abstract Despite potent anti-malarial treatment, mortality rates associated with severe falciparum malaria remain high. To attempt to improve outcome, several trials have assessed a variety of potential adjunctive therapeutics, however none to date has been shown to be beneficial. This may be due, at least partly, to the therapeutics chosen and clinical trial design used. Here, we highlight three themes that could facilitate the choice and evaluation of putative adjuvant interventions for severe malaria, paving the way for their assessment in randomized controlled trials. Most clinical trials of adjunctive therapeutics to date have been underpowered due to the large number of participants required to reach mortality endpoints, rendering these study designs challenging and expensive to conduct. These limitations may be mitigated by the use of risk-stratification of participants and application of surrogate endpoints. Appropriate surrogate endpoints include direct measures of pathways causally involved in the pathobiology of severe and fatal malaria, including markers of host immune and endothelial activation and microcirculatory dysfunction. We propose using circulating markers of these pathways to identify high-risk participants that would be most likely to benefit from adjunctive therapy, and further by adopting these biomarkers as surrogate endpoints; moreover, choosing interventions that target deleterious host immune responses that directly contribute to microcirculatory dysfunction, multi-organ dysfunction and death; and, finally, prioritizing where possible, drugs that act on these pathways that are already approved by the FDA, or other regulators, for other indications, and are known to be safe in target populations, including children. An emerging understanding of the critical role of the host response in severe malaria pathogenesis may facilitate both clinical trial design and the search of effective adjunctive therapeutics. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 19 1 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Severe malaria Angiopoietin-2 Immune and endothelial activation Microvascular dysfunction Host-biomarkers Surrogate endpoints Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
spellingShingle |
Severe malaria Angiopoietin-2 Immune and endothelial activation Microvascular dysfunction Host-biomarkers Surrogate endpoints Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Rosauro Varo Clara Erice Sydney Johnson Quique Bassat Kevin C. Kain Clinical trials to assess adjuvant therapeutics for severe malaria |
topic_facet |
Severe malaria Angiopoietin-2 Immune and endothelial activation Microvascular dysfunction Host-biomarkers Surrogate endpoints Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Despite potent anti-malarial treatment, mortality rates associated with severe falciparum malaria remain high. To attempt to improve outcome, several trials have assessed a variety of potential adjunctive therapeutics, however none to date has been shown to be beneficial. This may be due, at least partly, to the therapeutics chosen and clinical trial design used. Here, we highlight three themes that could facilitate the choice and evaluation of putative adjuvant interventions for severe malaria, paving the way for their assessment in randomized controlled trials. Most clinical trials of adjunctive therapeutics to date have been underpowered due to the large number of participants required to reach mortality endpoints, rendering these study designs challenging and expensive to conduct. These limitations may be mitigated by the use of risk-stratification of participants and application of surrogate endpoints. Appropriate surrogate endpoints include direct measures of pathways causally involved in the pathobiology of severe and fatal malaria, including markers of host immune and endothelial activation and microcirculatory dysfunction. We propose using circulating markers of these pathways to identify high-risk participants that would be most likely to benefit from adjunctive therapy, and further by adopting these biomarkers as surrogate endpoints; moreover, choosing interventions that target deleterious host immune responses that directly contribute to microcirculatory dysfunction, multi-organ dysfunction and death; and, finally, prioritizing where possible, drugs that act on these pathways that are already approved by the FDA, or other regulators, for other indications, and are known to be safe in target populations, including children. An emerging understanding of the critical role of the host response in severe malaria pathogenesis may facilitate both clinical trial design and the search of effective adjunctive therapeutics. |
format |
Article in Journal/Newspaper |
author |
Rosauro Varo Clara Erice Sydney Johnson Quique Bassat Kevin C. Kain |
author_facet |
Rosauro Varo Clara Erice Sydney Johnson Quique Bassat Kevin C. Kain |
author_sort |
Rosauro Varo |
title |
Clinical trials to assess adjuvant therapeutics for severe malaria |
title_short |
Clinical trials to assess adjuvant therapeutics for severe malaria |
title_full |
Clinical trials to assess adjuvant therapeutics for severe malaria |
title_fullStr |
Clinical trials to assess adjuvant therapeutics for severe malaria |
title_full_unstemmed |
Clinical trials to assess adjuvant therapeutics for severe malaria |
title_sort |
clinical trials to assess adjuvant therapeutics for severe malaria |
publisher |
BMC |
publishDate |
2020 |
url |
https://doi.org/10.1186/s12936-020-03340-3 https://doaj.org/article/86d42e349f614e7db049f4afa0bd9cdb |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 19, Iss 1, Pp 1-6 (2020) |
op_relation |
http://link.springer.com/article/10.1186/s12936-020-03340-3 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-020-03340-3 1475-2875 https://doaj.org/article/86d42e349f614e7db049f4afa0bd9cdb |
op_doi |
https://doi.org/10.1186/s12936-020-03340-3 |
container_title |
Malaria Journal |
container_volume |
19 |
container_issue |
1 |
_version_ |
1766346641065902080 |